Background Rheumatoid arthritis (RA) is an inflammatory joint disease affecting multiples tissues including the soft connective tissue surrounding the joints as well as the cardiovascular system. C4M is a biomarker of type IV collagen degradation, which is solely released from the basement membrane of, for example, the vasculature system. C4M was tested in the phase III clinical trial LITHE and was found to be a biomarker of disease activity and radiographic burden.
Objectives The aim of this study was to replicate and validate previous findings of C4M by measuring patient samples from the OSKIRA phase III clinical trials.
Methods OSKIRA 1, 2 and 3 (NCT01197521; NCT01197534; NCT01197755) (n=543) were all phase 3, randomized, double-blind, placebo-controlled studies of fostamatinib on a MTX background including RA patients with moderate to severe disease. Only baseline serum samples from the placebo arms were assessed. Patient population differed between the studies in that patients had inadequate response to: MTX (OSKIRA 1), DMARDs (OSKIRA 2) and single anti-TNF-α treatment (OSKIRA 3). Disease activity was assessed by disease activity score 28 (DAS28), swollen joint count 28 (SJC28), tender joint count 28 (TJC28) and health assessment questionnaire (HAQ). Radiographic Status was evaluated by joint space narrowing (JSN), erosion score (ERN) and mTSS. Serum C4M was measured in fasting serum by solid-phase competitive ELISA. Spearman rank correlations were applied to investigate the association between C4M and clinical parameters. Independent t-tests were applied for intergroup comparisons. Data that did not meet the criteria of normal distribution were log transformed prior to t-tests.
Results Demographics were comparable for the three OSKIRA studies and the placebo groups of each were therefore pooled together. Baseline levels of C4M were significantly correlated with the disease activity parameters DAS28 (r=0.377, p=0.0001), HAQ (r=0.206, p<0.0001), TJC28 (r=0.117, p=0.0068) and SJC28 (r=0.166, p=0.0001) and radiographic scores: ERN (r=0.135, p=0.003), mTSS (0.151, p=0.001) and JSN (r=0.152, p=0.001). There were no significant correlations between C4M and sex, age or BMI. There were no significant differences in C4M2 measurements in escapers versus non escapers or at baseline compared to the concentrations measured at week 24.
Conclusions The OSKIRA studies support previous findings of the LITHE study. C4M is highly associated with disease activity as well as radiographic progression level in patients with RA. Basement membrane remodelling, measured by C4M, appears to be highly important to the pathogenesis of RA. Further studies may reveal if alterations in basement membrane are linked to vascular dysfunction in patients with RA.
Disclosure of Interest None declared
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